JP5914246B2 - Method for purifying brinzolamide - Google Patents

Description

  The present invention relates to brinzolamide (chemical name: (R) -3,4-dihydro-4-ethylamino-2- (3-methoxypropyl) -2H-thieno [3,2-e]-useful as a glaucoma therapeutic agent. 1,2-thiazine-6-sulfonamido-1,1-dioxide).

  Following formula (1)

Is used as a therapeutic agent for glaucoma having a carbonic acid dehydrogenase inhibitory action. As a manufacturing method of this brinzolamide, following formula (2)

(S) -3,4-dihydro-4-hydroxy-2- (3-methoxypropyl) -2H-thieno [3,2-e] -1,2-thiazine-6-sulfonamide-1, A method of producing from 1-dioxide (hereinafter also referred to as a sulfonamide) is generally known.

  That is, the carbon atom at the 6-position of the sulfonamide {hereinafter abbreviated as C (6). } Is protected to form an imidate (step 1), and the carbon atom at the 4-position of the imidate (hereinafter abbreviated as C (4)). } Is activated (step 2), the activated hydroxyl group at the C (4) site is replaced with an amine, and the protecting group is removed from the sulfonamide functional group at the C (6) site to form brinzolamide Is generally known (Step 3) (Patent Document 1 and Non-Patent Document 1). In the above method, the reaction in Step 1 is performed by refluxing a sulfonamide compound and an acetonitrile solution of lower alkyl orthoacetate such as excess trimethyl orthoacetate for 12 to 48 hours. In the activation of Step 2, after removing the solvent, the solvent is replaced with tetrahydrofuran, and the imidate obtained in Step 1 is converted to methanesulfonic anhydride or chloride in the presence of a base such as pyridine, triethylamine or dimethylaminopyridine. 1. It is carried out by reacting with sulfonyl chloride such as p-toluenesulfonyl, p-bromotoluenesulfonyl chloride or p-nitrotoluenesulfonyl chloride, and preferably at a temperature of −10 to 15 ° C. for 1 to 4 hours. 0-2.5 equivalents of p-toluenesulfonyl chloride and triethylamine are used. Further, in Step 3, the brinzolamide was isolated by acid-base treatment of the product after adding 10-40 equivalents of the appropriate amine to the cold solution and reacting for 8-60 hours.

  On the other hand, brinzolamide used as a drug substance is usually required to have a purity of 99.5% or more and a melting point of around 131 ° C. Therefore, the brinzolamide crude body obtained by the above method needs to be purified with high purity. Patent Document 1 and Non-Patent Document 1 describe a method of purifying an isolated brinzolamide crude product by crystallization from 2-propanol. In this method, the purity of the obtained brinzolamide crystal is 97. .4% (Non-patent Document 1), and the melting point was 125 to 127 ° C. (Patent Document 1), which was not satisfactory.

  As another purification method, Patent Document 2 describes a method of recrystallization from ethanol. However, as a result of studies by the present inventors, a method of recrystallization from ethanol yielded a brinzolamide crystal having a purity of 99.5% or more, but its melting point was 125 to 127 ° C., which was also satisfactory. Was not obtained.

  The thus obtained brinzolamide crystal having a melting point of 125 to 127 ° C. shows the same crystal form as that of the brinzolamide crystal having a melting point of about 131 ° C. Therefore, it is the impurity contained in the brinzolamide crystal that has a low melting point. It is thought that there is an influence. Although the purity of the brinzolamide crystals obtained by the above method is as high as 99.5% or higher, the measurement of the purity is based on liquid chromatography. It was considered that impurities that could not be detected by a simple purity measurement method were included.

Japanese Patent No. 2854798 International Publication No. 2008/062463

Organic Process Research & Development (1999), 3 (2), 114-120.

  Accordingly, it is an object of the present invention to provide a method for producing high purity brinzolamide.

The present inventors diligently studied to solve the above problems. As a result, in the method of recrystallizing brinzolamide from ethanol, impurities can be efficiently removed by performing activated carbon treatment before recrystallization operation and adding seed crystals during further crystallization. I found out that I can do it.
That is, the present invention relates to (R) -3,4-dihydro-4-ethylamino-2- (3-methoxypropyl) -2H-thieno [3,2-e] -1,2-thiazine-6-sulfone. A step of mixing a crude product of amide-1,1-dioxide (brinzolamide) and ethanol to prepare a first solution comprising the ethanol solution of the crude product, the first solution and activated carbon having a liquid temperature of 60 to 80 Activated carbon treatment step of separating activated carbon after mixing while maintaining at ° C. to obtain a second solution, (R) -3,4-dihydro-4-ethylamino-2- (3) using seed crystals from the second solution -Methoxypropyl) -2H-thieno [3,2-e] -1,2-thiazine-6-sulfonamido-1,1-dioxide (brinzolamide) crystallizing step is included. It is a method.
Moreover, in this invention, it is preferable to perform the said crystallization process 2-4 times, and it is preferable to add a seed crystal at 45-55 degreeC in the said recrystallization operation.

  According to the present invention, by purifying a brinzolamide crude product by a specific method, a high-purity brinzolamide crystal having a melting point of about 131 ° C. and a purity of 99.6% or more, more preferably 99.8% or more is stabilized. Can be manufactured automatically.

The present invention is a step of mixing a brinzolamide crude and ethanol to prepare a first solution comprising the crude ethanol solution, while maintaining the liquid temperature at 60 to 80 ° C. An activated carbon treatment step of separating activated carbon after mixing to obtain a second solution, and a crystallization step of precipitating brinzolamide crystals from the second solution using seed crystals.
Hereinafter, details of the present invention will be described in order.

(Brinzolamide crude)
The brinzolamide crude product used in the present invention is not particularly limited, and a known method, for example, one produced by the method described in Patent Document 1 is used, and one produced by the following production method is used. You can also. In the following production method, a brinzolamide having a purity of 97 to 99% can be stably obtained, and by using this as a crude brinzolamide of the present invention, a higher-purity brinzolamide crystal can be stably produced. . Details of the production method will be described below.

(Method for producing brinzolamide crude product)
In the production method, the brinzolamide crude product is produced from the sulfonamide product through a reaction step, a separation step, and an isolation step. Hereinafter, details of each process will be described.

1. Reaction Step In the reaction step, the hydroxyl group bonded to the C (4) site of the sulfonamide is activated and then ethylaminated to obtain a reaction mixture containing the target product. That is, the method preferably comprises an activation step of activating the hydroxyl group bonded to the C (4) site of the starting compound, and an amination step of generating the target compound by substituting the activated hydroxyl group with ethylamine. It can be carried out. Moreover, you may perform the protection process which protects the sulfonamide group couple | bonded with C (6) site | part of the raw material compound and produces | generates the protected raw material compound before an activation process as needed. When a protection process is performed, a deprotection process may be performed either before or after the amination process after the activation process.

  In the protection step, protection of the sulfonamide group bonded to the C (6) site of the raw material compound is preferably performed by heating and mixing the raw material compound and a lower alkyl orthoacetate as a protective agent in a reaction solvent. it can. As the lower alkyl orthoacetate, trimethyl orthoacetate is particularly preferably used because the alcohol produced as a by-product in the reaction can be easily removed. The reaction solvent is not particularly limited as long as it is an inert solvent that does not participate in the reaction. However, it is particularly preferable to use ethyl acetate or acetonitrile because the reaction temperature can be easily controlled. The reaction conditions may be appropriately determined. Usually, the raw material compound, 1.0 to 1.5 moles of lower alkyl orthoacetate with respect to 1 mole of the raw material compound, and 1.5 to 1.5 parts with respect to 1 part by weight of the raw material compound. What is necessary is just to mix 10 mass parts reaction solvent and to make it react for 1 to 24 hours under recirculation | reflux. By performing such a reaction, a raw material compound in which the sulfonamide group bonded to the C (6) site is protected (hereinafter also referred to as imidate) can be obtained.

  The activation of the hydroxyl group in the activation step is, for example, obtaining an imidate concentrate by distilling off the solvent after completion of the protection step, and cooling the solution obtained by dissolving the concentrate in an organic solvent such as tetrahydrofuran. Then, 1.0 to 1.5 mol of a sulfonyl chloride compound is added to the solution with respect to 1 mol of the imidate, and the mixture is stirred at a temperature of −10 to 15 ° C. for 1 to 4 hours. By such an operation, a raw material compound or imidate body (hereinafter also referred to as a sulfonyl body) in which the C (4) moiety is sulfonylated can be obtained. Since the compound is dissolved in the reaction solution, the amination reaction can be performed by adding ethylamine to the reaction solution. As the sulfonyl chloride compound, it is preferable to use p-toluenesulfonyl chloride because the reaction time in the subsequent desorption step can be shortened and the yield is improved.

  The deprotection reaction in the deprotection step may be performed either before or after the amination step as long as it is after the activation step. Since the activating group is not affected by the deprotecting material, it is better to carry out at the same time as the amination step or after the amination step. The deprotection method may be any reaction as long as it is a general method for deprotecting lower alkyl orthoacetate, but it is particularly preferable to use water in a 70% ethylamine aqueous solution because it can be carried out simultaneously with the ethylation reaction described later.

  The amination step comprises reacting a sulfonyl compound with ethylamine. Any form of ethylamine may be used, but it is particularly preferable to use a 70% aqueous solution of ethylamine because it is readily available, the deprotection step described above can be performed simultaneously with the amination, and the concentration of ethylamine is high and the reaction efficiency is high. . In the reaction (amination reaction) between the sulfonyl compound and ethylamine, ethylamine was added to the reaction solution cooled to 10 ° C. or less so that the amount of ethylamine was 10 to 50 mol relative to 1 mol of the sulfonyl compound, and the cooling was maintained. The reaction can be suitably carried out by reacting for a predetermined time. There is no particular problem if the reaction temperature is 10 ° C. or lower, but 5 ° C. or lower is preferable because the reaction purity improves at low temperatures. Since the whole reaction rate also falls when temperature falls, 0 to 5 degreeC is especially good. The cooling is particularly preferably performed until the reaction progress is 90% or more, but may be heated according to the reaction progress as necessary. However, when the reaction progress at the time of heating to 10 ° C. or higher is low, the range of improvement in the yield and purity of the target compound obtained is small. In this case, the degree of reaction progress refers to the sum of the target compound and the protected target compound divided by the total of the target compound, the protected target compound, the sulfonyl compound, and the deprotected sulfonyl compound.

2. Separation step In the separation step, the crude product of the target compound is separated from the reaction mixture obtained in the step. Separation here means separating the reaction solvent and water-soluble impurities in the reaction mixture from the crude product comprising the target compound containing organic impurities. The crude product of the target compound means a target compound containing organic impurities (such as organic by-products and residual organic solvents) as main impurities, and is usually a solid having a purity of about 65 to 85%. Or it means a viscous liquid. Separation of the crude product from the reaction mixture is accomplished by adding a base such as sodium hydrogen carbonate to the reaction solution, which is the reaction mixture, and then separating the organic components using an organic solvent (extraction solvent) such as ethyl acetate. If necessary, washing with water and drying (moisture removal) are performed, and the extraction solvent is distilled off and concentrated.

3. Isolation Step In the isolation step, the obtained target compound is dissolved in an organic solvent, and the target compound is crystallized from the corresponding mixed solution. The solvent to be used may be a single solvent or a mixed solvent, but a mixed solution of alcohol and a nonpolar solvent, or alcohol is preferable. 2-Propanol is particularly preferable because the purity and yield of the target compound obtained are high. The amount of solvent used at this time is usually 1 to 50 parts by mass with respect to 1 part by mass of the coarse body. Considering the batch yield and the operability improvement of the filtration step, 2 to 10 parts by mass is preferable. In order to crystallize the target compound from the solution thus prepared, the solution may be cooled. Depending on the temperature at which the solution is prepared, when the nonpolar solvent is added after the crude product is dissolved in alcohol, the target product may crystallize with the addition of the nonpolar solvent. is there. Usually, it is preferable to perform crystallization by heating the solution containing the crude product to 50 ° C. to 100 ° C. to completely dissolve the crude product and then cooling the solution to −10 ° C. to 20 ° C.

  In the present invention, a high-purity brinzolamide crystal can be produced by performing the operation of the present invention on the brinzolamide crude product. That is, the present invention comprises a step of mixing a brinzolamide crude body and ethanol to prepare a first solution comprising the crude ethanol solution, and maintaining the liquid temperature at 60 to 80 ° C. The activated carbon treatment step of separating the activated carbon after mixing to obtain a second solution, and the crystallization step of precipitating brinzolamide crystals from the second solution using seed crystals. Hereinafter, details of each operation of the present invention will be described.

(First solution adjustment process)
In the present invention, first, a brinzolamide crude product and ethanol are mixed to prepare a first solution composed of an ethanol solution of the crude product.
In the present invention, the method for preparing the first solution is not particularly limited. Specifically, the brinzolamide crude body and ethanol are mixed and heated as necessary to dissolve the crude body and A first solution can be obtained. Although the temperature at the time of heating will not be specifically limited if it is the temperature which the said rough body melt | dissolves, Since the next activated carbon treatment process can be performed as it is, it is preferable.
In addition, the amount of ethanol used as a solvent in the present invention is preferably 4 to 16 parts by mass, and 8 to 12 parts by mass with respect to 1 part by mass of the brinzolamide crude material in consideration of purification ability, operability and the like. More preferably, it is a part.

(Activated carbon treatment process)
The activated carbon treatment step of the present invention is a step of obtaining the second solution by separating the activated carbon after mixing the first solution and activated carbon while maintaining the liquid temperature at 60 to 80 ° C. In the present invention, by performing this step before the following crystallization step, impurities that are not removed in the following crystallization step are effectively removed, and by using seed crystals in the following crystallization step, the melting point is reduced. High purity brinzolamide crystals can be obtained at 131 ° C.
In the activated carbon treatment step of the present invention, specifically, the first solution and activated carbon are mixed, and the mixed solution is filtered while hot to remove the activated carbon to obtain a second solution. In this step, it is preferable to stir the mixed solution. Moreover, it is preferable to wash | clean the removed activated carbon with 70-80 degreeC ethanol, and to make the obtained washing | cleaning liquid into a 2nd solution with the filtrate obtained by hot filtration.

The amount of activated carbon used in the activated carbon treatment step is determined by considering the purity improved by the activated carbon treatment, the degree of purity improvement in the subsequent crystallization, the operability, and the secondary decolorization effect. It is preferable that it is 0.05-0.5 mass part with respect to 1 mass part of coarse bodies, and it is more preferable that it is 0.1-0.3 weight part. Moreover, in the said process, it is preferable that the quantity of ethanol used by washing | cleaning is 1-4 mass parts.
Furthermore, since the brinzolamide may be decomposed by carrying out the activated carbon treatment step for a long time, the first solution and the activated carbon are mixed and preferably stirred for 5 minutes to 2 hours, for 10 to 20 minutes. It is more preferable to stir.
Using the second solution obtained in the activated carbon treatment step, the next crystallization step can be performed as it is.

(Crystallization process)
The crystallization step of the present invention is a step of precipitating brinzolamide crystals from the second solution using seed crystals.
Specifically, in the crystallization step of the present invention, the second solution is cooled to 45 to 55 ° C., seed crystals are added, and crystals of brinzolamide are precipitated. Further, after adding the seed crystal, the temperature of the solution is lowered at 6 to 60 ° C./hour, preferably 25 to 35 ° C./hour while stirring the mixed solution, and 0 to 20 ° C., more preferably 0 to 5 ° C. for 1 hour. It is preferable to hold the above to precipitate crystals. This mixed solution is filtered to remove ethanol, and the obtained crystals are washed 1 to 3 times with ethanol at 0 to 25 ° C. to obtain brinzolamide crystals. The yield in one crystallization step is 90 to 95%.
The seed crystal used in the crystallization step is not particularly limited as long as it is a brinzolamide crystal, and the amount of the seed crystal used is 0.0001 to 0.001 mass relative to 1 part by mass of the brinzolamide crude body. Part is preferable from the viewpoint of dispersibility of the seed crystals. Moreover, it is preferable that the quantity of ethanol used by the said washing | cleaning is 0.8-2 mass parts.
Moreover, in this invention, it is preferable to perform the said crystallization process 2-4 times. By performing the crystallization process twice, the purity of the brinzolamide crystal can be increased to 99.8% or higher, and by performing the process three to four times, the purity can be increased to 99.9% or higher.

  In the present invention, in the second and subsequent crystallization steps, the crystals of brinzolamide obtained in the previous crystallization step and ethanol are mixed to form a second solution, and the crystals of brinzolamide are obtained using seed crystals from the second solution. To precipitate. Specifically, the crystal of brinzolamide obtained in the previous crystallization step and ethanol are mixed and heated as necessary to form a second solution comprising the ethanol solution of the crystal, and the first crystallization step It is preferable to obtain crystals by precipitating crystals by the same operation as in, and solid-liquid separation. When obtaining the second solution, the temperature when heating is not particularly limited as long as the crystal is dissolved, but is not particularly limited as long as it is higher than the seed crystal addition temperature of 45 to 55 ° C. Any temperature at which the crystal dissolves may be used. Further, in the second and subsequent crystallization steps, the amount of ethanol used as a solvent is 4 to 16 parts by mass of ethanol with respect to 1 part by mass of brinzolamide in consideration of yield, purity, operability, and the like. Preferably, it is 8-12 mass parts.

  According to the present invention, as described above, by performing the recrystallization operation using the seed crystal following the activated carbon treatment operation, the brinzolamide crystal having a melting point of about 131 ° C. and a purity of 99.6% or more is stabilized. Can be manufactured automatically. Furthermore, by performing the recrystallization operation 2 to 4 times, the purity of the obtained brinzolamide crystal can be made 99.8% or more, and further 99.9% or more.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
In addition, the purity measurement of the brinzolamide obtained by the Example and the comparative example was performed as follows.

<Method for measuring purity of brinzolamide, etc.>
Apparatus: Alliance model e2695-2489 manufactured by WATERS
Detector: UV absorptiometer (measurement wavelength: 254 nm)
Column: GL Science Co., Ltd. product name Inertsil CN-3, particle size 5 μm, inner diameter 4.6 mm, length 25 cm,
Column temperature: 40 ° C. Constant temperature mobile phase: n-hexane / ethanol = 80/20
Flow rate: 1.0 ml / min Measurement time: 45 minutes

Example 1
To the first solution obtained by adding 8 g of ethanol to 1 g of brinzolamide crude body (purity 98.25%) and dissolving by heating at 70 ° C., 0.2 g of activated carbon was added and stirred for 10 minutes, and then the activated carbon was removed by filtration operation. The activated carbon was washed with 4 g of ethanol at 70 ° C., and the filtrate and the washing solution were combined to obtain a second solution (activated carbon treatment step). The second solution was gradually cooled to 50 ° C. while stirring, 0.001 g of seed crystals was added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 0.8 g of ethanol at 0 ° C. to obtain 0.9 g of brinzolamide crystals (purity 99.64%) (first crystallization step). 10.7 g of ethanol was added to the crystals and dissolved by heating at 70 ° C. The solution was gradually cooled to 50 ° C. while stirring, 0.0009 g of seed crystals were added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 0.71 g of ethanol at 0 ° C. to obtain 0.82 g of brinzolamide crystals (purity 99.88%) (the second crystallization step). 9.7 g of ethanol was added to the crystals and dissolved by heating at 70 ° C. The solution was gradually cooled to 50 ° C. with stirring, 0.0008 g of seed crystals were added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. Precipitated crystals were obtained by filtration, washed twice with 0.65 g of ethanol at 0 ° C. and dried to obtain 0.75 g of brinzolamide crystals (purity 99.93%) (the third crystallization step). The obtained brinzolamide crystal had a melting point of 131 ° C. and an optical purity of 100.0% ee. Met.

Example 2
After adding 7.6 g of activated carbon to the first solution obtained by adding ethanol 300 g to 38.02 g of brinzolamide crude (purity 98.66%) at 70 ° C. and stirring for 10 minutes, the activated carbon was removed by filtration. The activated carbon was washed with 150 g of ethanol at 70 ° C., and the filtrate and the washing solution were combined to obtain a second solution (activated carbon treatment step). The second solution was gradually cooled to 50 ° C. while stirring, 0.038 g of seed crystals were added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 30 g of ethanol at 0 ° C. to obtain 34.2 g of brinzolamide crystals (purity 99.68%) (first crystallization step). 405 g of ethanol was added to the crystals and dissolved by heating at 70 ° C. The solution was gradually cooled to 50 ° C. while stirring, 0.034 g of seed crystals were added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. Precipitated crystals were obtained by filtration and washed twice with 27 g of ethanol at 0 ° C. to obtain 31.5 g of brinzolamide crystals (purity 99.81%) (second crystallization step). To this crystal, 249 g of ethanol was added and dissolved by heating at 70 ° C. The solution was gradually cooled to 50 ° C. with stirring, 0.031 g of seed crystals were added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. Precipitated crystals were obtained by filtration, washed twice with 25 g of ethanol at 0 ° C., and dried to obtain 29.0 g of brinzolamide crystals (purity 99.95%) (the third crystallization step). The obtained brinzolamide crystal had a melting point of 131 ° C. and an optical purity of 100.0% ee. Met.

Comparative Example 1 (No activated carbon treatment process, seed crystal unused)
A first solution obtained by adding 12 g of ethanol to 1 g of brinzolamide crude product (purity 98.25%) and dissolving by heating at 70 ° C. was gradually cooled with stirring, cooled to 0 ° C., and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 0.8 g of ethanol at 0 ° C. to obtain 0.9 g of brinzolamide crystals (purity 99.51%). The obtained brinzolamide crystals had a melting point of 127 ° C. and an optical purity of 99.9% ee. Met.

Comparative Example 2 (no seed crystals used)
After adding 40g of ethanol to 15.07g of brinzolamide crude body (purity 98.24%) and heating and dissolving at 70 ° C, 1.3g of activated carbon was added and stirred for 10 minutes, and then the activated carbon was removed by filtration. The activated carbon was washed with 10 g of ethanol at 70 ° C., and the filtrate and the washing solution were combined to obtain a second solution (activated carbon treatment step). The second solution was cooled to 0 ° C. with stirring and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 10 g of ethanol at 0 ° C. to obtain 12.83 g of brinzolamide crystals (purity 99.34%) (first crystallization step). To this crystal, 45 g of ethanol was added and dissolved by heating at 70 ° C. It cooled to 0 degreeC and stirred for 1 hour. Precipitated crystals were obtained by filtration and washed twice with 9.5 g of ethanol at 0 ° C. to obtain 11.2 g of brinzolamide crystals (purity 99.57%) (the second crystallization step). 44 g of ethanol was added to the crystals and dissolved by heating at 70 ° C. It cooled to 0 degreeC and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 9 g of ethanol at 0 ° C. to obtain 10.7 g of brinzolamide crystals (purity 99.79%) (the third crystallization step). The obtained brinzolamide crystal had a melting point of 129 ° C. and an optical purity of 99.9% ee. Met.

Comparative Example 3 (no activated carbon treatment process)
The first solution obtained by adding 197 g of ethanol to 12.49 g of brinzolamide crude product (purity 98.24%) and heating and dissolving at 70 ° C. is gradually cooled to 50 ° C. with stirring, and 0.012 g of seed crystals is added. Then, it was cooled to 0 ° C. over 100 minutes and stirred for 1 hour. Precipitated crystals were obtained by filtration and washed twice with 9.9 g of ethanol at 0 ° C. to obtain 11.24 g (purity 98.46%) of brinzolamide crystals (first crystallization step). 177 g of ethanol was added to the crystals and dissolved by heating at 70 ° C. The solution was gradually cooled to 50 ° C. while stirring, 0.011 g of seed crystals were added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 8.9 g of ethanol at 0 ° C. to obtain 10.15 g (purity 99.25%) of brinzolamide crystals (the second crystallization step). 130 g of ethanol was added to the crystals and dissolved by heating at 70 ° C. The solution was gradually cooled to 50 ° C. with stirring, 0.010 g of seed crystals were added, and then cooled to 0 ° C. over 100 minutes and stirred for 1 hour. Precipitated crystals were obtained by filtration, washed twice with 8 g of ethanol at 0 ° C., and dried to obtain 9.14 g of brinzolamide crystals (purity 99.39%) (the third crystallization step). The obtained brinzolamide crystal had a melting point of 128 ° C. and an optical purity of 99.8% ee. Met.

Comparative Example 4 (No activated carbon treatment step, crystallization step with 2-propanol)
A first solution obtained by adding 135 g of 2-propanol to 17.12 g of a brinzolamide crude product (purity 98.64%) and heating and dissolving at 70 ° C. was cooled to 0 ° C. with stirring and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 14 g of 2-propanol at 0 ° C. to obtain 16.75 g of brinzolamide crystals (purity 98.95%) (first crystallization step). To this crystal, 107 g of 2-propanol was added and dissolved by heating at 70 ° C. The solution was cooled to 0 ° C. with stirring and stirred for 1 hour. Precipitated crystals were obtained by filtration and washed twice with 11 g of 2-propanol at 0 ° C. to obtain 15.61 g of brinzolamide crystals (purity 99.02%) (the second crystallization step). 2-propanol 98g was added to this crystal | crystallization, and it heat-dissolved at 70 degreeC. The solution was cooled to 0 ° C. with stirring and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 12 g of 2-propanol at 0 ° C. to obtain 15.53 g of brinzolamide crystals (purity 99.21%) (the third crystallization step). The obtained brinzolamide crystal had a melting point of 125 ° C. and an optical purity of 99.8% ee. Met.

Comparative Example 5 (crystallization step with 2-propanol)
To the first solution obtained by adding 100 g of 2-propanol to 15.53 g of brinzolamide crude product (purity 99.21%) and heating and dissolving at 70 ° C. After adding 5 g of activated carbon and stirring for 10 minutes, the activated carbon was removed by filtration. The activated carbon was washed with 20 g of 2-propanol at 70 ° C., and the filtrate and the washing solution were combined to obtain a second solution (activated carbon treatment step). The second solution was cooled to 0 ° C. with stirring and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 12 g of 2-propanol at 0 ° C. to obtain 10.19 g (purity 99.84%) of brinzolamide crystals (first crystallization step). To this crystal, 120 g of 2-propanol was added and dissolved by heating at 70 ° C. The solution was cooled to 0 ° C. with stirring and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 13 g of 2-propanol at 0 ° C. to obtain 8.09 g of brinzolamide crystals (purity 99.86%) (the second crystallization step). 99 g of 2-propanol was added to the crystals and dissolved by heating at 70 ° C. The solution was cooled to 0 ° C. with stirring and stirred for 1 hour. The precipitated crystals were obtained by filtration and washed twice with 9 g of 2-propanol at 0 ° C. to obtain 7.44 g of brinzolamide crystals (purity 99.88%) (the third crystallization step). The obtained brinzolamide crystals had a melting point of 127 ° C. and an optical purity of 99.9% ee. Met.

Claims (3)

  (R) -3,4-dihydro-4-ethylamino-2- (3-methoxypropyl) -2H-thieno [3,2-e] -1,2-thiazine-6-sulfonamide-1,1- A step of mixing a crude product of dioxide and ethanol to prepare a first solution comprising the crude ethanol solution, and mixing the first solution and activated carbon while maintaining the liquid temperature at 60 to 80 ° C. Activated carbon treatment step to obtain a second solution by separating (R) -3,4-dihydro-4-ethylamino-2- (3-methoxypropyl) -2H-thieno using seed crystals from the second solution (R) -3,4- characterized in that it comprises a crystallization step of precipitating crystals of [3,2-e] -1,2-thiazine-6-sulfonamide-1,1-dioxide. Dihydro-4-ethylamino-2- (3-methoxypropyl Pills) -2H- thieno [3,2-e] -1,2- thiazine-6-sulfonamide-1,1-dioxide The method of manufacturing.   The method according to claim 1, wherein the crystallization step is performed 2 to 4 times.   The method according to claim 1 or 2, wherein seed crystals are added at 45 to 55 ° C in the crystallization step.